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Review of Health Studies Relevant to Lawrence Livermore National Laboratory and the Surrounding Community

LAWRENCE LIVERMORE NATIONAL LABORATORY, MAIN SITE (USDOE)
LIVERMORE, ALAMEDA COUNTY, CALIFORNIA

EXECUTIVE SUMMARY

Lawrence Livermore National Laboratory (LLNL), a research facility conducting nuclear weapons
research and development, is located in Livermore, California, in the San Francisco Bay Area. In 1987,
the LLNL Site was placed on the federal National Priorities List ("Superfund"). Releases of volatile organic chemicals, metals, plutonium and tritium have occurred at this site.

The California Department of Health Services (CDHS) has produced this health consultation with support
from the Agency for Toxic Substances and Disease Registry (ATSDR). The review of available health
outcome data for plausible outcomes and outcomes of community concern is a standard component of the
ATSDR health assessment process, and this review was requested by members of the site team, which
consisted of community residents, stakeholders, and agencies working with CDHS at this site.

This health consultation summarizes health studies and reviews regarding LLNL and is not intended to
provide a comprehensive analysis of those studies. Although in most cases the study is simply
summarized, in some cases we comment directly on the analysis to provide the reader with a fuller
interpretation, and these comments are noted as our own. The studies fall into several areas: (1) studies of
cancerincidence in workers (many on melanoma, a type of skin cancer); (2) case-control studies of
workers to identify possible causes of elevated melanoma; (3) reviews of studies; (4) studies of cancer
incidence among community members; and (5) a review of birth defects in the community.

In general, the incidence of cancer among LLNL employees was not higher than expected. However,
studies from the 1970s through the mid-1980s found melanoma rates among employees of the LLNL to
be approximately three times higher than expected. Some of this excess might be partly due to earlier
diagnosis of LLNL employees, as publicity about melanoma prompted heightened awareness. The search
for workplace risk factors for melanoma found several factors to be associated, including work around
ionizing radiation.

Ionizing radiation is radiation that has enough energy to strip away electrons from atoms or break some
chemical bonds. Although there may not be adverse health effects, cells may become malignant and the
chance of cancer increases. The main types of ionizing radiation are alpha, beta, and gamma (e.g., nuclear
explosions are one source of gamma rays, plutonium emits alpha rays, and tritium emits beta rays).
Tritium is a radioactive isotope of hydrogen that binds with oxygen to form tritiated water, which can be
readily absorbed through the skin, inhaled, or ingested. In the Livermore community, historic tritium
releases from LLNL are one possible exposure source for the community to ionizing radiation.

Overall rates of cancer in community residents were not elevated over three decades. However, statistical
reviews of health data among community residents found elevations of melanoma among children and
young adults. More recently, melanoma rates among residents of Livermore were not significantly
elevated, nor were more birth defects found than expected.

In 1984, LLNL instituted on-site medical screening for melanoma in order to detect and treat pre-cancerous skin lesions. LLNL has stated that melanoma rates have fallen to Bay Area averages since
1985.(1) Data on melanoma rates should be periodically reviewed to see if this trend is continuing. Also,
because of the findings that working around radiation was associated with higher risk of melanoma within
the LLNL workforce, it would be useful for future epidemiological studies of radiation in other settings to consider investigating melanoma specifically.

This document was originally issued as a Public Comment Draft in February 2003 and has been modified in response to comments received. Original comments and responses are included in the Appendices.

BACKGROUND AND STATEMENT OF ISSUE

Lawrence Livermore National Laboratory Site

Lawrence Livermore National Laboratory (LLNL), a high-energy research facility conducting nuclear
weapons research and development, is located in Livermore, California, in the San Francisco Bay Area
(Figure 1, Appendix A). The site was originally used by the military as a flight training base and aircraft
assembly and repair facility, before the Atomic Energy Commission converted the former base to LLNL in 1951 (1).

LLNL was placed on the National Priorities List (NPL; "Superfund") of hazardous waste sites in 1987
because of groundwater contamination from volatile organic chemicals (1). Spills and other releases of
metals, fuel hydrocarbons, plutonium and tritium also had occurred at the site (1,2). Developing and testing nuclear weapons and conducting other energy research at LLNL has involved numerous and varied chemicals, processes, and radiation sources (3).

Above-background levels of plutonium in a community park near LLNL were discovered, and an
investigation was conducted to determine how the contamination might have occurred (4). It has also been
determined that plutonium-contaminated sludge (due to releases from LLNL) from the municipal water
treatment plant was distributed to the public and other entities for use as a soil amendment in the
community. The practice of distributing sludge occurred from the late 1950s until the early 1970s (5). The
levels of plutonium were estimated and evaluated by ATSDR, and deemed well below a level that would
cause health problems (5), but as the data are incomplete, the possibility that the
evaluation may not be definitive in all cases has been raised (6).

Most of the tritium released from LLNL has been to the air, with the Tritium Facility as the major source
of these smaller, routine, day-to-day airborne releases, which occur in the course of conducting
experiments with radioactive gases (7). Other sources include sewage discharge (7).
Tritium has been found in rainwater at LLNL, with levels seven times the drinking water standard (8).
Elevations of tritium were also observed in off-site rainwater samples, and the levels were found to be
lower than the on-site samples (8). Besides the routine releases, there were several large
releases of tritium to the Livermore community, one in 1965 and one in 1970 (9). An expert panel
determined that 80% of the releases from LLNL occurred during those two accidents (9).
These air releases created completed exposure pathways with the nearby population (a completed
exposure pathway means that the contaminant reached a population that had contact with it) (9).

Ionizing Radiation

Ionizing radiation is radiation that has enough energy to strip away electrons from atoms or break some
chemical bonds, creating ions which can be hazardous to living tissue (10,11). In some cases there may not be adverse effects (11). The body has ways to repair
some cell damage, but if cells become malignant, the chance of cancer increases (11).
The main types of ionizing radiation are alpha, beta, and gamma (e.g., nuclear explosions are one source
of gamma rays, plutonium emits alpha rays, and tritium emits beta rays) (10). Tritium is
a radioactive isotope of hydrogen that binds with oxygen to form tritiated water, which can be readily absorbed through the skin, inhaled, or ingested. (Additional information on ionizing radiation is included in Appendix D.)

Public Health Assessment at LLNL Site

CDHS, in a coop process with ATSDR, began a health assessment process in September 1996 to evaluate
whether or not site-related contaminants from LLNL were affecting the local community. At the start of
the process, CDHS convened a site team of community members, stakeholders, and agency
representatives to help identify and prioritize health topics to be addressed, review and comment on
documents prepared about the site, and act as a conduit between the site team and the agency or
community that each member represents. The review of available health outcome data for plausible
outcomes and outcomes of community concerns is a standard component of the ATSDR health
assessment process, and a health consultation reviewing and summarizing the different health studies
relevant to the Livermore community was requested by members of the site team. The CDHS has
prepared this health consultation with support from the ATSDR. ATSDR is preparing a document which
will summarize the evaluation of site-related contaminants.

Children's Health Considerations

CDHS and ATSDR recognize that in communities with contaminated water, soil,
air, or food, infants and children can be more sensitive than adults to chemical
exposures. This sensitivity results from several factors: (1) children might
have higher exposures to environmental toxins because, pound for pound of body
weight, children drink more water, eat more food, and breathe more air than
adults; (2) children play outdoors close to the ground, increasing their exposure
to toxins in dust, soil, surface
water, and ambient
air; (3) children have a tendency to put their hands in their mounts, thus they
might ingest potentially contaminated soil particles at higher rates than adults;
(4) children are shorter than adults, which means they can breathe dust, soil,
and vapors close to the ground; (5) children's bodies are rapidly growing and
developing, thus they can sustain permanent damage if toxic exposures occur
during critical growth states; and (6) children and teenagers more readily than
adults may disregard no trespassing signs and wander onto restricted property.
Regarding ionizing radiation exposure specifically, because children are growing
more rapidly, they have more cells dividing, posing a greater opportunity for
radiation exposure to disturb this process (11).

Scope and Purpose of this Health Consultation

This health consultation (HC) summarizes publicly available information from a number of health studies
and health data reviews regarding LLNL and the surrounding community. The document is not intended
to provide a comprehensive analysis of those studies. The HC includes both worker and community
studies of cancer because findings among workers may be relevant as an indication of potential effects in
the community. Although in most cases, the studies (or critiques) are simply summarized, in a few cases it
seemed relevant to comment directly on the analysis to provide the reader with a fuller interpretation of
the findings, and these comments are indicated as our own.

Community health studies of cancer incidence among residents in the area; and

Birth defects (review of incidence in the community).

This review first summarizes LLNL worker studies. Included are both studies of cancer incidence rates
and case-control investigations to determine potential workplace risk factors for melanoma. Many of the
studies concern melanoma, which became the subject of a series of investigations that found an excess of
this cancer in the LLNL workforce. Further investigations were undertaken in an attempt to verify the
previous findings, assess whether studies had been correctly performed, understand the importance of
personal risk factors (such as lifestyle or physical characteristics), evaluate alternative explanations for the
elevation (such as aspects of data reporting), and identify specific workplace exposures that could account
for the elevation (such as radiation or chemicals). Reviews of the key studies were conducted to evaluate
them and confirm the results, which are reported here as well. All existing community studies are also
reviewed; these include reports on cancer incidence and birth defects. A summary table of studies
reviewed is also provided; these are listed approximately in chronological order (Table 1, Appendix B).

This document was originally issued as a Public Comment Draft in February 2003, and has been modified
in response to comments received. Most of the comments fell in several main areas, so we have written a
general response to each area that addresses a number of specific points. These responses are in Appendix C. Additional responses to minor comments can be found in Table 4. The original comments received are
also included (Appendix F).

Community Health Concerns

Some community members were concerned about what they felt was an excess of cancers among people
in the community. In addition to mentioning melanoma, other cancers of concern cited by residents
included leukemia, brain cancer, and ovarian cancer. Some community members were concerned about
and/or knew of children with birth defects. Other conditions mentioned included fibromyalgia, irritable
bowel syndrome, psoriasis, rashes, diarrhea, stomach ache, headache, and fatigue. Community health
concerns are discussed more comprehensively in a health consultation on that topic (12). Because this
health consultation is a review of existing information, only cancer and birth defects are addressed.

Although incidence of and mortality from many cancers have been decreasing in California, cancer
overall is still the second leading cause of death (13). According to current rates, one of every two men and
two of every five women will develop some form of invasive cancer in their lifetimes
(13). Breast cancer is the most common cancer among women, prostate cancer is the
most common cancer among men, and lung cancer is the second most common cancer for both men and
women (13).

History of Melanoma Concerns at LLNL and in Livermore

Community concern about LLNL-related melanoma first came to the attention of CDHS in 1978, when a
prominent LLNL scientist died of melanoma. In a 5-year period, there had been 13 LLNL employees who
had been diagnosed with melanoma (14). These findings prompted the chief laboratory physician of LLNL
to request that the Resource for Cancer Epidemiology (RCE) of CDHS (now the Cancer Surveillance Section of the California Cancer Registry) investigate the incidence of melanoma among LLNL
employees (3,14). These
events also raised questions about children in the area who had developed the disease around the same
time (14).

In 1984, LLNL established a workplace melanoma screening program to ensure that employees were
regularly screened for skin diseases (15). All employees were systematically asked to examine their moles
(a risk factor for melanoma) and report their findings to LLNL Health Services personnel. A physician
still runs a weekly clinic at LLNL to examine employees and surgically remove any suspicious lesions
before they develop further. Many melanomas can be prevented if earlier skin changes are identified and
treated, and treatment will be more successful for melanomas identified in early stages
(15).

Malignant Melanoma of the Skin

Melanoma is one of three common types of skin cancer; the other two are basal cell carcinoma, and
squamous cell carcinoma. These skin cancers usually develop in the outer layer of skin, the epidermis.
Basal and squamous cell carcinoma are often grouped together as non-melanoma skin cancer. The top
layer of the epidermis is made of dead cells that contain keratin. The cells that produce keratin can
develop into squamous cell cancer. The deeper layers of the epidermis has cells called melanocytes,
which produce melanin, the pigment made when skin is exposed to sun. These are the cells that become
cancerous in malignant melanoma. At the bottom of the epidermis are the basal cells, which are the cells
that normal skin develops from, but can develop into basal cell cancer, which is the most common type of
skin cancer. The thickness of the epidermis and dermis (the skin layer below the epidermis) together can
vary from 2-4 millimeters (mm).

Epidemiology of Malignant Melanoma of the Skin

Although malignant melanoma of the skin (cutaneous melanoma) was once considered rare, its incidence
has risen dramatically (16). In 2002, 1.3 million Americans were diagnosed with skin cancer; although
only around 4% of these skin cancers were melanoma (26). In the United States, the risk
of developing this cancer is estimated to be about one of every nine persons (17). Recent data show 11.5
new cases per year for every 100,000 persons in California (13). Over time, incidence
rates have increased among white populations around the world (18), a development that does not appear to be merely the result of greater public awareness (17).

This increase in rates has also been followed by an increase in the number of well-designed studies
covering occupational and other exposures, and constitutional risk factors (i.e., physical characteristics
such as skin type) (26). Information from these studies has provided evidence for the role
of solar ultraviolet light exposure in development of melanoma (19), as well as evidence implicating
exposure to artificial sources of ultraviolet light (20). There is also some evidence that persons with
suppressed immune systems may be at greater risk for melanoma, such as persons who had received
immunosuppressive treatment for a primary cancer (21), or organ transplant recipients (22).

Melanoma incidence and mortality rates vary by social class, with higher rates in the upper social classes (23,24,25). This is hypothesized to be associated with lifestyle factors, perhaps because wealthy individuals
might be more likely to vacation in sunny locations (19,24). Constitutional risk factors must also be considered:
higher risk is associated in persons with light or red hair, and persons who have a tendency to sunburn
easily (23).

Having a large number of nevi (moles) is now recognized as one of the strongest predictors of melanoma
risk (26,50). However, atypical dysplastic nevi (irregularly shaped moles) appear not only
a marker for increased risk of melanoma, but a potential precursor of melanoma (27). This means that they
share a common causal pathway, such as sun exposure, but nevi would develop before melanoma, as an
intermediate step in the evolution of melanoma (26).

Ionizing radiation is considered among other possible occupational exposures as to its ability to cause
melanoma, but the evidence has been mixed (28). Because melanoma has not been historically associated
with ionizing radiation (only with ultraviolet radiation) (28,37), opportunities could have been lost in rigorously assessing this relationship. For
example, a 1990 report of atomic bomb survivors reports that skin cancer except melanoma was evaluated (29). It was similarly not evaluated in a large study of British atomic weapons workers (30), nor another
study of radiation workers in the United States (31).

Consideration of Biological Plausibility for Melanoma being caused by Ionizing Radiation

Ionizing radiation is known to cause many human cancers (28). Because ionizing
radiation removes electrons from atoms, it has the ability to produce permanent damage after a relatively
small amount of energy is absorbed (28). Radiation is thought to induce carcinogenic
change by either 1) inducing mutations and altering the structure of single genes of chromosomes; 2)
changing gene expression without mutations; or 3) weakening the immune system, allowing certain
viruses in turn to cause cancer (32). [Please refer also to the Appendix D for information on ionizing
radiation.] Although almost all cancers can be caused by radiation, the amount of radiation required to
induce a particular type of cancer varies (33). Some cancers are very common in the population generally,
but are not easily caused by radiation (relatively more radiation is required to induce them) (e.g., colon);
others are infrequent but can be caused by lower amounts of radiation (e.g., thyroid)
(33). In the opinion of CDHS, one possibility why melanoma has been overlooked in the
past is that even though it could be caused by ionizing radiation, it may not have been recognized because
it may not be as easily caused by radioactivity as other cancers. Another reason is that melanoma is much
less frequent in comparison to the other types of skin cancers, and detecting an increase in a frequent
event will be easier than in a rarer outcome, at least from a statistical perspective.

As discussed above, releases of a variety of chemicals and radionuclides have occurred at the LLNL site,
including plutonium and tritium. In the event of human contact with tritium, because it is essentially a
type of water molecule, it is easily absorbed by the skin (10), or can damage living
tissues and organs it comes in contact with after inhalation or ingestion (34). In the opinion of CDHS, the
fact that tritium can be absorbed into the skin supports the plausibility that this type of exposure could
contribute to melanoma, although it is not known at this time if this exposure is related to melanoma
occurrence.

Plutonium-239 is another site contaminant. Although plutonium is considered to be usually absorbed by
the dead, outer layer of human skin (11), recent research on skin decontamination
methods found that when plutonium was applied to skin samples, most of its radioactivity was found to
be in the epidermis, with 2-4% of its radioactivity penetrating through the epidermis to reach the deeper, dermal skin layer (35). Depth of penetration would in part presumably depend on individual skin
thickness. Because the melanocytes (the cells which develop into melanoma) are located within the
epidermis, the fact that melanoma develops from the melanocytes and that plutonium-239 may penetrate
into and beyond the skin layer containing melanocytes, would support the plausibility that plutonium
exposure may have the potential to contribute to the development of melanoma, in the view of CDHS.

DISCUSSION

LLNL WORKER STUDIES

Cancer Incidence Data

Incidence is a measure that is used to quantify the number of new cases of a disease that develop in a
population at risk during a specific time interval (36). Studies can measure disease incidence among
different groups of individuals who are defined by the presence or absence of exposure to a suspected risk
factor. The incidence of disease can then be compared between these groups as a method of evaluating the
relationship between disease and exposure. This comparison between two incidence rates is called an
"incidence rate ratio."

Table 2 shows the elevation in melanoma in the LLNL workforce compared to other populations, from
different studies. Figure 2 shows melanoma cases among LLNL workers over time. This figure, and the
studies which contributed these data, are discussed later in this report.

Original Investigation of a Perceived Excess of Melanoma Among LLNL Employees (A Study of Cancer
Incidence in Lawrence Livermore Laboratory Employees [Report #1]; Malignant Melanoma Among
Employees of Lawrence Livermore National Laboratory (37,38))

The initial study (Report #1) of melanoma incidence among LLNL employees was conducted by the RCE
and LLNL. The findings were issued as a report by CDHS in 1980 (37), and subsequently as a journal article in 1981 (38). The study examined incidence of melanoma among the 5,100 white employees of
LLNL during 1972-1977 who lived in Alameda or Contra Costa counties. For each study year, members
were grouped by 5-year age group, sex, and census tract of residence. Each year of residence in the study
area by a study member (employee of LLNL during that year) was counted as 1 year of observed time for
the group to which the member belonged. The number of observed cancer cases was compared to the
number that would be expected. The expected number was based on the rates among all white persons of
the same age group and sex who lived in the same census tracts as the employees during the given year
(of employee diagnosis).

Nineteen cases of malignant melanoma were identified at LLNL during the study period. The number of
melanomas observed was three times higher than expected. The statistical likelihood of an elevation of
this magnitude occurring by chance alone is about two in 100,000 (for males).

The statistical likelihood of certain results occurring by chance can also
be expressed using a confidence interval (CI), which represents the range within
which the true magnitude of effect lies with a certain degree of assurance (often
95% is chosen) (36). For this analysis, the best estimate of the incidence ratio
of melanoma among males at LLNL was 3 (i.e., males at LLNL were 3 times more
likely to have melanoma compared to Alameda and Contra Costa county residents
during 1972-1977). However, a confidence interval can add information about
how much uncertainty exists in this estimatethe wider the confidence interval,
the less precise the estimate. The width of the confidence interval reflects
the sample sizethe greater the number of people studied, the more precise
the estimate becomes. The degree of precision for the estimate of 3 is shown
by its confidence interval, which indicates that with 95% assurance (from a
statistical perspective), the true incidence ratio lies between 1.5 and 5.9
(i.e., the true incidence ratio is at least 50% higher than expected and might
be nearly six times higher than expected.)

Another component of the analysis assessed the incidence rate for malignant melanoma among white
males aged 20-64 in the LLNL study group. The rate was compared to the corresponding rate for all
white males in Alameda County (excluding LLNL employees). The LLNL worker rate was 48.8 cases per
100,000 persons versus 11.7 cases per 100,000 persons for Alameda County. Thus, melanoma incidence
among male LLNL employees in the study group was over 4 times higher than that of other white males
in Alameda County. It also was elevated when compared to the community rate in the cities of Livermore
and Pleasanton, excluding LLNL workers. This community rate was 13.5 cases per 100,000 persons,
indicating male LLNL workers experienced about 3.6 times the melanoma rate of the surrounding
community.

A second cancer incidence review spanning a greater number of years (1969-1980) was undertaken by
RCE to assess whether there was an excess of melanoma or any other cancer in this occupational cohort.
The study examined the incidence of cancer among active employees of LLNL between 20-69 years of
age. Person-years of observation were categorized by sex and 5-year age groups. The age categories
contributing the greatest number of person years were in the middle of this age range, with the 40-44 year
old category highest among these. The San Francisco-Oakland Standard Metropolitan Statistical Area
(SMSA) rates were used for comparison. For all types of cancer combined, the ratio of the observed
number of cancer cases to the number expected was 0.95, indicating that fewer cases of cancer occurred
than would typically be expected for this population. Among the approximately 100 comparisons made,
the only statistically significant excesses found were salivary gland tumors (among females), nervous
system tumors other than brain tumors (among males), and malignant melanoma of the skin (males and
females). The observed number of melanomas was over 3 times that expected. Although the excess of
salivary gland tumors was statistically significant among women, this was based on only a few cases. For
other nervous system tumors (other than brain cancer), three cases occurred, but less than one was
expected (0.23). When a large number of analyses are made simultaneously, it is possible that some will
be elevated by chance alone. Thus, one possibility is that some of these findings could have been due to
chance.

Cancers were also analyzed according to their "radiosensitivity;" that is, how likely they are to be caused
by radiation exposure. Cancers were further grouped according to whether they were considered "highly
radiosensitive" or "moderately radiosensitive." No excess cancer was found among the highly
radiosensitive category (the ratio of the observed to expected was 0.86). The "moderately radiosensitive"
cancers include lung and female breast, and the ratio of observed to expected cancers was significantly
less than expected (0.62).

Men at LLNL had less lung cancer than the general population (the difference was statistically
significant). More educated men tend to smoke less than the general population, and, as the LLNL
workforce may be generally well educated, this could be a reason for this difference. Thus, in general, the
study did not find cancer rates, other than melanoma, to be elevated in active LLNL employees.

Investigation of Melanoma Elevation and Alternative Explanations Using Kaiser Permanente Medical
Care Program (KPMCP) Population (The Possible Effect of Increased Surveillance on the Incidence of
Malignant Melanoma (40))

The question of whether melanoma rates were elevated among LLNL employees was also examined
among members of Kaiser Permanente Medical Care Program (KPMCP), a large, prepaid health plan
with eight facilities in the San Francisco Bay Area. A substantial portion of the LLNL worker population
subscribed to KPMCP. Melanoma incidence among LLNL-employee KPMCP members was compared
with rates among other KPMCP members. The years studied were 1976-1980.

Melanoma incidence rates for LLNL employees were uniformly higher than rates among members at any
of the other KPMCP facilities, including others in sunny areas such as Walnut Creek, Vallejo, Santa Clara
and Sacramento. The rates by facility included LLNL employee cases, so the true difference would be
expected to be higher. Compared to the KPMCP members at one of the facilities (Walnut Creek), the
relative risk of melanoma for LLNL employees was 3.2 (95% confidence interval (CI) = 1.7-6.0). This
means that for an LLNL employee the risk of having melanoma was 3.2 times higher than the risk for
melanoma among all KPMCP members attending the Walnut Creek facility.

In addition to evaluating LLNL employees, the study calculated melanoma rates among LLNL
dependents who were KPMCP members. The relative risk of melanoma for LLNL dependents was non-significantly elevated at 2.1 (95% CI = 0.9-4.7). The number of cases was small, and from a statistical
perspective, this result could have occurred by chance.

The number of physician visits for skin appointments was also analyzed to assess if there was a difference
in care between LLNL employees and other KPMCP members. This analysis for the years 1974-1980
found LLNL employees had a greater number of physician visits for skin appointments to KPMCP than
non-LLNL employees, and that the number of biopsies for skin lesions among persons without melanoma
was greater among LLNL employees than KPMCP members. In 1976 and earlier, (before publicity about
the melanoma excess), the number of biopsies was somewhat greater among LLNL employees, but not
significantly so. After 1976, the number of biopsies was significantly greater among LLNL employees.
The authors suggested that awareness of LLNL's excess melanoma incidence could have increased the
propensity of physicians to take biopsies among LLNL employees, which would contribute to the excess
incidence of melanoma. Alternatively, although this was not suggested by the authors, it would be
possible that higher rates of skin conditions among LLNL employees led to a need for more frequent
biopsies, e.g., the greater presence of pre-cancerous skin cell changes. Finally, the authors also stated that
there could be an environmental agent (or agents) in the laboratory environment that could be responsible
for an underlying increase in melanoma incidence.

In a letter to Lancet, LLNL, with Drs. Jeffrey Schneider and Richard Sagebiel of the University of
California at San Francisco's (UCSF) dermatology and pathology department, published data on the
distribution of melanoma thickness among employees at LLNL over three time periods: 1969-1975 ("pre-awareness"), 1977-1984 ("early awareness"), and 1984-1986 ("aggressive surveillance"). They showed
that the rate of melanoma increased by time period, and that lesion thickness decreased over these time
periods as well. They suggested that the increasing proportion of thin melanomas is a result of greater
awareness within the population as well as the results of medical efforts to identify skin disease earlier.

Investigation of Alternative Explanations for Melanoma Elevation Using a Community Pathology
Laboratory for Comparison (Early Diagnosis of Cutaneous Malignant Melanoma at Lawrence Livermore
National Laboratory (42))

In an effort to understand possible reasons for the increase in melanoma incidence among employees,
LLNL conducted a study in collaboration with Dr. Schneider of UCSF. This study compared the
thickness of melanoma lesions in LLNL employees with other melanoma cases in the community. The
study used cases from 1976-1984. The study years were primarily after the original period for RCE
Report #1 (1972-1977) and after publicity had raised public awareness. Comparisons with lesions seen at
a community laboratory were made for 31 lesions from LLNL employees originally diagnosed with
melanoma, which were confirmed to have cutaneous malignant melanoma and had information available
on lesion thickness.

The average thickness of lesions diagnosed at LLNL was found to be thinner than those diagnosed in the
community (there were 476 community member lesions for which thickness information was available).
Initially during the 3-year period around 1976 there was little difference in tumor thickness between
LLNL and community lesions. However, subsequently lesion thickness declined in both the community
and LLNL lesions, although the LLNL decline was greater. The authors suggest that it is possible that
earlier diagnosis among LLNL employees would result in thinner lesions being reported and that this
might have contributed to the excess of melanoma seen among LLNL employees, at least in these years
following increased publicity and awareness.

Investigation of Alternative Explanations for Melanoma Elevation (Cutaneous Melanoma at Lawrence
Livermore National Laboratory: Comparison with Rates in Two San Francisco Bay Area Counties (43))

In collaboration with the Northern California Cancer Center and researchers at Stanford University,
LLNL undertook another study to investigate whether the increased melanoma rate was due to either (1)
under-reporting of community melanoma, or (2) heightened awareness of melanoma leading to early
detection of LLNL melanomas. LLNL employees from 1974-1985 were studied. Early detection could
lead to a greater number of cases that would otherwise not have been discovered until a later stage. (The
total number of cases would not change, but more of them would be discovered sooner and fewer
discovered later.)

The study also calculated incidence ratios for melanoma, finding rates to be 2.9 times higher than
expected for men at LLNL and 2.4 times higher for women. When the tumors were separated into
different thickness categories, the excess was found among the thinner categories.

To address the first hypothesis of under-reporting, investigators identified several dermatopathology
laboratories that the state cancer registry had not included. Although this resulted in finding some
additional community melanoma cases that had not been reported in the registry, the number of cases was
small and did not explain the apparent excess incidence.

To address the second hypothesis of possible early detection, the analysis separated tumors by thickness
to look at rates within thickness categories for LLNL employees. The analysis was conducted only among
cases for which thickness information was available. Among LLNL employees, excess melanomas were
found in the categories of very thin tumors (<0.75 mm) and medium thin tumors (0.76-1.50 mm), but not
in moderate to thick tumors (>1.50 mm). The authors conclude that "...no excess of melanoma is observed
if we limit our attention to thicker, more invasive melanomas." The authors suggested as a possible
interpretation that melanomas among LLNL employees were detected earlier (when they are still thin),
than those among community members, due to the educational campaign conducted by LLNL.

To evaluate whether this hypothesis is supported by the data, it is important to look at what happens to
rates in the next time period as well. If in reality no more LLNL tumors are occurring than usual, and the
apparent excess is only due to identifying tumors earlier at thinner stages, then we would expect that they
would be missing from the later time period during which they would otherwise have been counted. This
would mean that rates in the next time period would drop, because those early-detected tumors would be
absent, as they would have already been counted in the previous time period (when they were thinner).
However, although rates in this later time period decreased, they remained elevated, which would not
support the hypothesis that early detection was the reason for the increased melanomas.

However, there is one other possible alternative explanation that could reconcile the early detection
theory with the finding that rates did not drop in the subsequent time period. This would only be possible
if some thin but invasive tumors actually disappear. This hypothesis is based on the idea that some
melanomas do not develop into more invasive tumors but instead regress. The authors suggest this as a
possible explanation. Although this phenomenon exists, it is very rare (44), which does not suggest it
would account for the elevation.

In support of the idea that melanomas are detected earlier among LLNL employees than in the general
population, the authors pointed to two differences they view as noteworthy. First, they described the
proportion of very thin melanomas as increasing with calendar period, both at LLNL and in the
community, but more strongly at LLNL (early detection affecting LLNL and community equally could
not account for any difference in rates). Second, they concluded that lesions were thinner at LLNL
compared to the community.

CDHS conducted statistical tests of their reported numbers to assess whether there were differences in
lesion thickness between the two time periods, or between LLNL and the community, finding that any
differences could not be distinguished from chance in this small group of cases.(2) In our view, the findings
support the existence of an excess of melanoma in the LLNL workforce, but are also consistent with a
possible effect of early detection. Given the publicity concerning the cases of melanoma and the LLNL
screening program (in later years), it would not be unusual for lesions to have been thin, and it would
perhaps have been surprising if many LLNL cases continued undetected long enough to progress to
thicker, more advanced stages.

Investigation of Alternative Explanations for Melanoma Elevation Using KPMCP Population
(Surveillance Bias and the Excess Risk of Malignant Melanoma Among Employees of the Lawrence
Livermore National Laboratory (45))

A study was conducted among members of KPMCP to determine if early detection of melanomas among
LLNL employees (surveillance bias) was the reason for elevated rates. KPMCP's Division of Research, in
collaboration with others, conducted the study. They hypothesized that if surveillance were increased
among LLNL members, then biopsies would be performed at an earlier stage of tumor development and
the thickness of the tumors would be less than that of other KPMCP members. The study included 20
LLNL melanoma cases and 36 matched melanoma cases of KPMCP members and covered the years
1970-1984. The analysis compared tumor thickness between the early period before publicity (1970-76)
to a later time period (1977-1984). The analysis found that tumors of LLNL employees were thinner than
the comparison group until 1977, after which there was no difference, as the tumor thickness among the
non-LLNL employees had decreased in the second time period of the study.

The authors cited a number of possible reasons for the difference in findings between this study and those
of the previous analysis by LLNL with Dr. Schneider (Dr. Schneider's study found LLNL melanomas to
be thinner than his comparison group during his study period [1976-1984]). One possibility is that the
two studies included somewhat different groups of participants. Also, some very thin lesions were
excluded in the KPMCP's study, as they were not considered melanomas by the blinded, three-person
panel of expert dermatopathologists who reviewed the slides. Another possible explanation is potential
differences in the nature of the comparison population. The LLNL-Schneider study used cases referred to
a laboratory, and it is not known if the laboratory population was representative of cases overall.

The authors concluded their findings were consistent with an effect of surveillance bias, contributing to
the excess melanoma rates up to around 1976, but did not support a role for surveillance bias in
explaining the excess incidence after that time.

LLNL Announces Completion of New Cancer Review (Health Review Reported in Press: "Lab Workers
During 1974-1997 Have High Rate of Cancer" (46,47))

Most recently, a review of cancer rates among LLNL employees compared to persons in the five-county
Bay Area was completed on behalf of LLNL by an outside consultant. The review covered the years
1974-1997, and was limited to diagnoses that occurred during the time of LLNL employment. This
summary is based on information contained in news articles published in November 2001 that contained
some report findings, but stated that the report was not yet available. CDHS requested this report,
however, as of this time of preparation of this report, per LLNL, the study is pending publication in a
journal article, and so is not yet publicly available. The study reportedly found that there were overall
fewer cases of cancer than expected among LLNL employees, for both men and women. The press
release also stated that the analysis found that men who worked at LLNL during the years covered had a
38% higher rate of melanoma, although the frequency of melanoma has declined in the past 15 years,
reportedly falling to Bay Area averages since 1985. Another finding presented was that testicular cancer
was 107% higher than expected among LLNL employees.

The study also reportedly found a statistically lower rate of "invasive genital organ cancer in women."
"Genital organ cancer" would include cervical cancer. As cervical cancer is primarily caused by a
sexually transmitted virus, the main risk factors are social/behavioral (48). A low rate of cervical cancer
would be expected for a well-educated population with good access to health care, such as LLNL.

A summary of melanoma incidence rate ratios among LLNL workers from different studies is shown in
Table 2. A value of 1.0 means the rate was not elevated in comparison to what would be expected based
on a standard or comparison population. Values above 1.0 indicate elevated melanoma rates (more melanoma occurred than expected). Elevations in melanoma rates exist for both
men and women, within different time periods, and using different comparison groups. The consistency
of this findings lends support to its validity.

Similarly, this elevation is portrayed in Figure 2, which shows the number of melanomas among LLNL
employees over time, separating those that were in situ (non-invasive) and those that were invasive. The
figure is a reproduction of one published in the LLNL journal article of their case-control study
(3). The figure displays lines representing the number of expected in situ and invasive
melanomas. The actual number that occurred exceeds the expected for both invasive and in situ melanoma. This shows an excess of melanoma that was not confined to thin tumors, suggesting that the excess was not simply due to greater detection among LLNL employees.

Case Control Data: Search for Workplace Risk Factors

A case-control study is a type of analytic epidemiological study in which participants are selected on the
basis of whether or not they have the disease that is being studied (36). The groups are then compared to assess the proportion in each group with a history of a certain
exposure or a particular risk characteristic.

The initial investigation by RCE (Report #1) of melanoma among LLNL employees also included a small
case-control study of the 19 cases of melanoma that were identified among employees. The study sought
to identify workplace risk factors associated with melanoma. Random selection from all other LLNL
employees of the same sex, race, 5-year age group, and area of residence was used to identify four
controls for each case. Cumulative gamma radiation exposure above background was compared between
cases and controls; other forms and specific sources of radiation (e.g., neutron, tritium, alpha, beta) were
not tested. No relationship was found between melanoma and monitored gamma radiation exposure
during LLNL employment, job classification as a scientist, or length of employment at LLNL. However,
an excess risk for melanoma was observed among chemists (relative risk=6.97; p-value=0.011).

Follow-Up Investigation of Melanoma Risk Factors (Report #3) (Investigation of an Excess of Melanoma
Among Employees of the Lawrence Livermore National Laboratory (49,50))

A broader and more rigorous case-control study using interviews was subsequently conducted by RCE to
gather more detailed information on familial cancer health history, socioeconomic status, sun exposure,
sun sensitivity, and occupational exposure history. The findings were issued first in a report in 1984
("Report #3") and later published as a journal article in 1997. This study involved all known cases of
malignant melanoma identified among active LLNL employees between 1969 and 1980. Random
selection was used to match the 31 cases to 110 controls from the appropriate age group (+ 5 years), race
(white), and sex as indicated in the annual employee file for the year of diagnosis of the respective case.
Data sources included the LLNL personnel and medical clinic records, excluding dosimetry records; a
mailed questionnaire; and an extensive in-person interview with the respondent (or next of kin if the
subject was deceased). Occupational data came from two sources: the personnel file classification of the
position type and project assignment, and the respondent's description of his or her duties and activities in
the work history portion of the interviews. Participants completed an occupational history, and a detailed
description of the jobs held during the 10-year period before the date of the melanoma diagnosis was
obtained. These jobs and activities were then coded according to the National Institute for Occupational
Safety and Health 1980 Census classification. The coder was blinded to the case versus control status of
each participant's data. Participants were also asked about their participation in nuclear events at specific
locations, and work assignments at Site 300, a weapons testing area about 15 miles from LLNL.

Several occupational factors were found to be strongly associated with risk status, resulting in an elevated
odds ratios (OR). The odds ratio is interpreted as: the likelihood of having a certain risk (e.g., having
chemist duties) among persons with melanoma compared to the likelihood of that risk among persons
without melanoma. Thus, the odds ratio for chemist duties was 8.0 (95% confidence interval: 1.4-46.0).
This is interpreted as: persons with melanoma were 8 times more likely to have had chemist duties than
those without melanoma. Other ORs were as follows: exposure to radioactive materials (OR=3.7; 95%
confidence interval: 1.6-8.6), and exposure to high explosives (OR=3.0; 95% confidence interval
1.0-9.5). In a multivariable model adjusting for occupational risk factors, the odds ratio of working
around radioactive materials (ever vs. never exposed) was 2.8 (95% confidence interval 1.1-7.1). After
adjustment for constitutional risk factors (i.e., physical traits such as skin fairness, tendency to sunburn)
and occupational risk factors of interest, the odds ratio associated with reported work around ionizing
radiation remained elevated, although this analysis did not quite reach statistical significance at the 0.05
level of significance (OR=2.3; 95% confidence interval: 1.0-7.6). This means that the odds of a person
with melanoma having worked around ionizing radiation was 2.3 times higher than that of a person
without melanoma after accounting for other risk factors. The authors concluded that the results were
sufficient to warrant additional studies of occupational factors and risk for malignant melanoma of the
skin.

Workplace Investigation of Increased Diagnosis of Malignant Melanoma Among Employees of Lawrence
Livermore National Laboratory (3,51)

In addition to the case-control studies described above, LLNL conducted its own case-control study of
melanoma. The findings were first issued in a LLNL document in 1994, and subsequently published as a
journal article in 1997. Although we present the conclusions that the LLNL authors made, this report also
discusses some key limitations in the study methodology we have identified.

The study included 69 cases among LLNL employees in 1969-1989, and collected extensive information
on a variety of known and hypothesized constitutional and occupational risk factors for melanoma.
Participation was limited to those living, so deceased participants in the earlier RCE study were not
included. In all, the cases in this study represent only a subset of all cases among LLNL employees. There were other differences between the studies, some of which are discussed
in the article in an assessment of what could have accounted for the difference in findings.

The LLNL study did not find occupational factors (exposure to ionizing radiation and chemicals) related
to melanoma risk among employees. LLNL found that constitutional factors explained most of the excess:
cases tended to sunburn more than controls, cases had more moles than controls, and controls sunbathed
more frequently than persons with melanoma. Although it would seem contradictory for controls (persons
who did not get melanoma) to sunbathe more frequently than the persons who got melanoma, the authors
suggested that cases avoided sunbathing probably due to their hypersensitivity to ultraviolet radiation.
This measures approximately the same characteristic as the first risk factor: cases tended to sunburn more
than controls. However, the second finding, that cases had more moles than controls, does not necessarily
mean that the excess melanoma was due to the moles; it could reflect an exposure that was causing both
the moles and the melanoma (52). LLNL's findings regarding constitutional factors were consistent with
those identified in the RCE Report #3 issued in 1984.

A LLNL nurse conducted a standardized interview regarding constitutional factors, and a dermatologist
conducted a physical examination. Participants underwent an "Occupational Factors Interview," which
consisted of an interview conducted by a former leader of the Hazards Control Department who had been
associated with LLNL and Lawrence Berkeley Laboratory for 40 years. The study used an open-ended
interview format to gather occupational information (rather than standardized questions), with a shorthand
reporter transcribing the conversation. The text was then reviewed and edited by the interviewee and the
investigators, and occupational factors were assigned numeric scores. The analysis also included a
computerized word-usage analysis to count the number of times in an interview a participant used various
exposure or melanoma-related words. Dosimetry records from the Hazards Control Department were also
obtained for gamma, neutron, tritium, skin, and hand radiation, as well as for doses before employment at
LLNL. The report presented extensive information on many variables; a detailed description of all the
material presented is beyond the scope of this review. The analysis did not present estimates of risk ratios
for any of the risk factors, which would have provided a quantitative assessment of the degree of risk
associated with a specific factor, such as having fair skin, or exposure to radiation. Several other key
factors limit the interpretation of the results.

First, in a case-control study, the selection of controls is fundamental in determining the overall results of
the study. LLNL used an algorithm to select controls on the basis of the best total score of five criteria:
(1) sex, (2) age, (3) start date at LLNL, (4) years of education, and (5) tenure at LLNL. Race was not a
matching factor, despite large disparities in risk by race (13). The factors were weighted
differentially.

This algorithm was created after modification based on the experience using the first 11 cases as a pilot
study. The 11 cases were re-analyzed along with the complete group using the modified criteria for the
actual study (51). Different algorithms would have resulted in
different controls. There were more than 16,000 possible controls from which to choose, and only one
control was selected per case. Which controls are selected is important as the overall results depend on the
characteristics of controls. The final algorithm emphasized some factors more heavily than others(3). For
example, sex was mismatched in 11 pairs, but even the pair with the poorest overall match score had a
start date and tenure within a month of each other. The results may have been quite different using a less
restrictive control selection process.

Secondly, it seems that within the LLNL workforce, matching on start date would have obscured critical
exposure information. This is because persons hired earlier had higher exposures to ionizing radiation and
chemicals than employees hired later, as the LLNL report states (51):

"Over the years, the LLNL workforce has seen a decrease in exposure to both chemicals and
ionizing radiation. Thus, employees with earlier start dates were likely to have higher exposures
than those with later start dates. We can demonstrate that this was true for all of the 138 members in our case control study."

Exposure assessment in occupational studies is typically a combination of job type, or job type and
concentration of substance to which a person is exposed, and duration of exposure. Matching on both start
date and employment tenure will increase the likelihood that major components of exposure assessment
will be the same (selecting controls with similar exposures to cases). Also, there would be no a priori
reason why cases would be more likely to have earlier start dates than controls, and understanding those
differences should be an important part of the data analysis.

Thus, in effect, the LLNL study appears to have matched cases to controls using a surrogate for exposure
(start date). Matching should not be used for any variable that one might wish to explore
(36). If a matching algorithm results in controls with similar exposures to cases, then one
cannot find exposure differences between case and control groups.

When publishing their report as a journal article, the investigators attempted to address the concern about
overmatching (e.g., matching on start date) by statistically assessing the relationship between start year,
years of education, and occupational exposure variables. The variables were based on those in the RCE
study: work with ionizing radiation, work at Site 300, work with photographic chemicals, presence at
Pacific Test Site, and duties as a chemist. The aim of the analysis was to investigate how much of the
variation in these occupational variables of interest was explained by the factors start year and education.

Highly statistically significant relationships were found between start year and the following four
occupational factors: ionizing radiation, work at Site 300, presence at Pacific Test Site, and photographic
chemicals. The relationship with chemist duties approached the standard level for statistical significance.
However, the authors concluded overmatching was not a problem because less than 30% of the total
variance of any of the occupational factor scores was explained by the factors start year and education.
Specifically, start year and education accounted for 27% of the variance of the factor "Presence at the
Pacific Test Site," and for 23% of the variance of the factor "Exposure to ionizing radiation."

The probability of a relationship this strong occurring by chance is less than 1 in 10,000 (i.e., for the
relationship between start year and the factors ionizing radiation, Site 300, and Pacific Test Site, p <0.0001). In our interpretation, the great unlikelihood of this strong an association occurring by chance
indicates that start year is in fact very strongly associated with the exposure variables (e.g., ionizing
radiation). (This interpretation is also supported by the above quotation regarding the decrease in ionizing
radiation and chemical exposures over time at LLNL.) Although it is possible that in an idealized dataset,
there would be adequate variability within a given start year for persons to have varying levels of
exposure, in reality at this site, start year appears to be so strongly correlated with radiation exposure and
that start year very closely represents this exposure.

In our view, matching on start date may have resulted in a group of controls with very similar exposures
as cases, which would have obscured a potential relationship between melanoma and ionizing radiation
(and any other occupational factors that correlated strongly with start year).

However, the study authors describe the use of matching on start date as a technique to prevent the effects
of confounding (a problem in epidemiologic studies that can obscure the relationship between the risk
factor and the outcome). Matching is often performed for potential confounding variables with known
associations with the outcome, like age, sex, and race. Because it is impossible to investigate how
matched factors might contribute to causing the disease, statistical adjustment during analysis (rather than
matching) is the preferred method of controlling confounding factors (36,53).

Confounding occurs when there is a factor other than the exposure being investigated that:

is associated with the exposure or factor being investigated; and

independently affects the risk of developing the disease (36).

A hypothetical example can be used to explain confounding. Suppose you are investigating if coffee
drinking causes lung cancer. You might find that coffee drinkers have more lung cancer. However, this
could be because coffee drinkers tend to smoke a lot more than other people, and it really is their smoking that is causing lung cancer. In this example:

smoking (the confounder) is associated with the factor being investigated (coffee drinking); and

Thus, in this situation, smoking is a confounder, and to understand the effects of coffee drinking on lung
cancer it is necessary to take into account smoking behavior. Even though smoking is a confounder in this
example, it would still be preferable to control for it in the analysis rather than match on it. That way, it is
possible to learn how smoking contributes to cancer, how coffee drinking may affect cancer, and exactly
how these factors may be related; a matched design precludes the possibility of gaining this information.

Applied to the LLNL situation, the two conditions that must be met if start date is a true confounder are:

start date (the possible confounder) is associated with the exposure being investigated (occupational factors such as ionizing radiation); and

start date independently affects the development of the disease (melanoma).

The first condition is met: start date is associated with occupational factors (e.g., ionizing radiation)
(occupational factor scores decrease with start date). What is not clear is whether the second condition is
met: whether start date itself independently affects the development of melanoma. The article states: "...we matched for start date in order to minimize the effects of a general change in the background
environment, which may contribute to the well-documented trend of increasing melanoma rates in recent
decades." It seems questionable whether start date is associated with whatever changes exist in the
general background environment that are responsible for the increased rate of melanoma over time. It is
of concern that start date seems likely to control for a general change in the LLNL environment, as this
would result in controlling for, not investigating, the exposures of interest. Age would be the more
appropriate control for general changes over time, and it is already a matching factor. It remains unclear
how start date would affect the risk of developing melanoma independently of its LLNL-related
exposures.

Given the analysis problems described above, we do not view the findings of this study as providing
evidence either to support or discount the potential relationship between melanoma and occupational exposures in the LLNL workforce.

Reviews of Worker Studies

Others conducted reviews of the studies by RCE in an effort to confirm results and understand if some
systematic bias or error had influenced those results. These are summarized below.

Independent Review by the State of California's Legislative Audit Committee of RCE Report #1
(37,38) (Joint Legislative Audit Committee
Report: "The Cancer Incidence Among Workers at the Lawrence Livermore Laboratory": A Synthesis of
Expert Reviews of the Study (54))

This review was conducted in 1980 in response to the original study by RCE (Report #1), which found
increased melanoma among LLNL employees (37). A panel of expert scientists and
physicians was asked to review the study and provide comments and recommendations to the California
Legislature's Joint Legislative Audit Committee. This broad-based group of experts concluded that the
findings of an unusually high melanoma rate appeared correct. The group opined that no conclusions
could be drawn about possible links to the LLNL environment, but that the findings were extremely
significant and required further study and attempt at explanation.

Review by Committee Convened by U.S. Department of Energy (Report of the Ad Hoc Advisory Board on
Melanoma (55))

In 1980, also in response to the RCE Report #1 (37), the Department of Energy
appointed an ad hoc committee of experts to review the study and its findings. The Board agreed with the
study findings that the rate of malignant melanoma among employees of LLNL was 3 to 4 times higher
than the general population. It maintained that preliminary efforts to explain the excess had not yet
succeeded, and recommended that the Department of Energy should support further epidemiological
investigations by CDHS.

Synthesis of Additional Reviews (Malignant Melanoma at a Scientific Laboratory: A Synthesis of
Reviewer's [sic] Comments on the Austin and Reynolds' Study of Employees at the Lawrence Livermore
National Laboratory (56))

This document produced in 1985 was commissioned by LLNL to synthesize the comments of seven
experts that LLNL had commissioned to review RCE Reports 1, 2, and 3
(37,38,39,49,50). Because the authors of this document sought to have the
experts' comments anonymous, this report reflects the opinions of the authors and uses selected quotes
from the reviewers.

The commissioned document addressed two questions: (1) if there was a real excess of melanoma among
employees; and (2) if the observed excess is causally related to factors in the occupational environment of
LLNL. The authors of the synthesis report stated that, in reference to the two questions, "The majority,
but by no means unanimous, opinion of the seven reviewers is that two problems remain unresolved...."
The authors reiterated the concept that possible spontaneous regression of melanomas was responsible
(i.e., early stage cancers disappearing rather than progressing). Another possible explanation, early
harvesting (identifying melanomas at earlier stages that would otherwise have been found later when they
were thicker), was dismissed as unlikely because a decrease in rates was not subsequently found. Most
reviewers also remained unconvinced about the likelihood of occupational factors being a cause, citing
the lack of a biological plausibility being previously established and the lack of a dose-response gradient.

However, in our view, the specific establishment of biological plausibility is outside the scope of an
epidemiological review, but cannot be ruled out (see earlier discussion of biological plausibility in the
background section). Similarly, the lack of a dose-response relationship, given the data limitations (e.g.,
badges measure only specific kinds of radiation; unrecorded exposures), does not rule out a relationship
either. The case-control study (Report #3) was the first systematic examination of the relationship
between radiation and melanoma, and the validity of the relationship withstood extensive testing in
several re-analyses (summarized below).

In 1987, at the request of LLNL, the University of North Carolina (UNC) produced this independent
review of RCE Report #3 (issued in 1984). The researchers systematically validated the study
(49,50) by performing several steps, including checking the accuracy of
the original data; validating the control selection; confirming the statistical calculations; and examining
the occupational factors using additional statistical models. As part of the effort to validate the study, the
reviewers also used data on individual radiation exposure as measured by badges worn by LLNL
employees (this information was not available to RCE).

Using data from the radiation badges, they found no association between exposure to ionizing radiation
and melanoma. They also used radiation badge information to classify job codes into those that were
radiation-related and those that were not. Using this criterion, they found that the melanoma cases were
significantly more likely than controls to have worked at jobs that were deemed radiation-related.

The study authors suggest several possible reasons for the lack of agreement between the findings based
on job codes vs. badge measurements. The accuracy of the badge data was investigated by safety
personnel at LLNL for one worker, finding that the radiation received by that worker could have been
considerably greater than what was recorded on the badge. It is also possible that badges are accurate, but
that they were not worn during the time of exposure. For example, exposures during off-site nuclear
testing would not necessarily be recorded or included in the LLNL file. Badge data may not have
included all relevant exposures, as only data for the previous 10 years was available. Also, there were
known problems in the computerized retrieval system for dosimetry, which was relatively new at the time.

The analysis found that after rigorous analytical validation and testing, three occupational factors remained associated with malignant melanoma at LLNL:

working around radioactive materials;

presence at Site 300; and

working around volatile photographic chemicals.

The reviewers concluded the study was generally well conceived, well conducted, and well analyzed,
although they considered the causal nature of the factors to be "overstated" in the RCE report. They
suggested this because the factors had been revealed in a hypothesis-generating study, and they would
have liked substantially more evidence from other studies before concluding that the factors were "true
risk factors." The reviewers then recommended further investigation regarding the potential relationship
between these exposures and risk for malignant melanoma.

In an extension of the previous UNC review (57), the independent
experts investigated the inconsistency between reported radiation exposure and individual dosimetry
readings, using dosimetry readings to create an exposure index. The findings were published in a journal
article in 1994. The analysis used a number of strategies to rigorously test the previous results.

The RCE Report #3 results were consistently confirmed. Melanoma case status was significantly
associated with risk of exposure based on an occupation-specific radiation index, as represented by an
odds ratio of 10.8 (95% confidence interval: 1.4-85.1). This association was confirmed in numerous
multivariate models; a multivariate model is a statistical method for taking into account several risk
factors at the same time. This is interpreted as: persons with melanoma were more than 10 times more
likely to have had radiation exposure (as measured by the occupational index) than persons without
melanoma, after accounting for other potential confounders. The robust nature of the results suggested to
the authors that the odds ratio for reported employment in proximity to radiation may be valid.

COMMUNITY HEALTH STUDIES

This section reviews cancer incidence studies among Livermore community residents. Cancer incidence
rate ratios from these health studies are shown in Table 3 in Appendix B. This table will be discussed later
in this report.

Initially, concern about exposure focused exclusively on identification of factors in the workplace,
lifestyle, or constitutional factors that might have resulted in increased melanoma rates among LLNL
employees. In the 1980s, research in the United Kingdom at a nuclear establishment found a higher than
expected number of cases of leukemia among children of male workers who were exposed to radiation
during a pre-conception period (59). In an attempt to see if a similar effect could be seen at another nuclear
facility, researchers undertook a review of cancer rates among children and young adults in the vicinity of
LLNL.

Investigation of Cancer Rates in Children and Young Adults in Livermore (Cancer Incidence Among
Children and Young Adults in Livermore, California: 1960-1991 (60))

This study was focused on leukemia and non-Hodgkin's lymphoma, the cancers found to be elevated in
the United Kingdom study. Cancer incidence was examined in two cohorts: (1) white children and young adults (to age 24) residing in Livermore, California, and diagnosed between 1960-1991; and (2)
white children and young adults (to age 24) born in Livermore, California, between 1960-1990, and
diagnosed between 1960-1991.

The overall rate for all types of cancer combined was 1.2, with a 95% confidence interval of 1.0-1.4,
indicating that the rate was not statistically different from 1.0 (indicating no elevation). Rates for the other
cancer groups evaluated were not found to be in excess: leukemia 1.2 (95% CI=0.7-1.7); non-Hodgkin's
lymphoma 0.7 (0.2-1.7); Hodgkin's disease 0.7 (0.3-1.5); and brain cancer 1.3 (0.8-2.1). The standardized
incidence ratio for brain cancer among children and young adult Livermore residents was elevated at a
level that reached statistical significance (3.0; 95% CI=1.4-5.8) during the earliest decade studied, 1960-1969, but then gradually diminished over the next two decades. Brain cancer has been noted to be
relatively sensitive to the effects of ionizing radiation (32).

However, the study found an excess of melanoma in young community residents. Among children and
young adults residing in Livermore, melanoma rates were 2.4 times higher than expected, and among
persons 24 years of age and under who had been born in Livermore, the rate was 6.4 times higher than
expected. Both results were statistically significant.

Investigation of Community Cancer Rates in Livermore (Cancer Incidence in Livermore: 1988-1993 (61))

Subsequently, a review of cancer rates in eight census tracts in Livermore was undertaken by the Cancer
Surveillance Section (formerly RCE) of CDHS. The years covered (1988-1993) were more recent than
the earlier investigation. The Cancer Surveillance Section examined cancers of all anatomical sites (as one
group), plus separately those cancer types well-known to be associated with exposure to radioactivity.
Those sites included: bone, female breast, brain, leukemia (excluding chronic lymphocytic leukemia,
which has not been associated with ionizing radiation), lung, prostate, and thyroid. Melanoma was also
reviewed, although it was not historically considered a radiation-induced cancer. The review included all
ages and was based on residence, and did not contain any information on whether cases were LLNL
employees or family members of employees. One census tract in the southeastern section of Livermore
(tract 4515) was of particular concern to residents.

In a cancer rate review, it is typical to calculate a confidence interval around the observed number of
cases to assess the statistical likelihood of a result (the number of observed cases of cancer) occurring by
chance. Consistent with the standard California cancer registry procedures, a 99% confidence interval was
used for this purpose; any difference between the observed and expected numbers is not statistically
distinguishable from chance if the expected number of cancers falls within the confidence interval for the
observed number of cancers.

The review found that the incidence of cancer among residents of the eight census tracts was similar to
the Bay Area as a whole: a total of 1295 cases were expected during this time period, and 1214 cases
occurred. The number of melanomas in the community was not elevated (51 expected vs. 56 observed.)
Similarly, in the census tract next to LLNL (4515), the overall number of cancers was not elevated: a total
of 285 cancer cases were expected, and 257 actually occurred. In census tract 4515, 18 melanomas were
diagnosed: seven in women (compared to five expected) and 11 in men (compared to six expected).
Although the number of melanomas was greater than the number expected, it fell within a range that could have occurred by chance.

Table 3 in Appendix B shows the incidence ratios of cancer among different groups of community
members studied. Confidence intervals are presented as well. (Please see discussion of confidence
intervals presented as part of the summary of Report #1, "A study of cancer incidence in Lawrence
Livermore Laboratory Employees.") Blank areas of the table reflect no data analyzed within that study.
The table reflects the general lack of cancer elevation among the community, with the notable exception
of melanoma. In addition to the main and consistent findings from the RCE/CDHS study of melanoma
elevation across time and within both cohorts evaluated, a smaller, non-statistically elevation was found
among dependents of LLNL employees who were KPMCP members.

BIRTH DEFECTS

(Birth Defects Around Livermore: 1983-1989 (62))

The California Birth Defects Monitoring Program of CDHS conducted a review of birth defects in the zip
codes around the Livermore area. The review covered the years 1983-1989, the only years the program
operated in Alameda County. The following data were reviewed: (1) the total number of birth defects; (2)
the number of birth defects that have been associated with ionizing radiation (on the basis of what has
been published in scientific literature), including chromosomal abnormalities, microcephaly, and
autosomal dominant mutations; and (3) number of other major birth defects. The overall rate of birth
defects was very similar to the statewide rate (2.5 per 100 live births in Livermore compared to 2.9 per
100 across the state). The numbers of specific birth defects were similar to or lower than statewide rates,
and the number of other major birth defects was not significantly greater than expected in Livermore.
(Specific numbers are not shown in order to protect confidentiality when the observed number of cases is less than six.)

SUMMARY AND CONCLUSIONS

In general, the incidence of cancer among LLNL employees was not higher than expected. However, a
number of studies from the 1970s through the mid-1980s consistently found melanoma rates among
employees of the LLNL to be approximately 3 times higher than expected.

Overall rates of cancer in community residents were not elevated over three decades (1960-1990).
However, among children and young adults residing in Livermore, the melanoma rate was over 2 times
higher than expected; and among children and young adults who had been born in Livermore, the rate
was over 6 times higher than expected. More recently, cancer rates among Livermore residents have been
found to be similar to the Bay Area as a whole, according to a report pending publication by LLNL. The number of melanoma cases occurring in a census tract
bordering LLNL was greater than expected, but statistically within a range that could have occurred by
chance.

In 1984, LLNL instituted an on-site medical surveillance program for melanoma. Early detection and
treatment would be expected to prevent melanomas, as precancerous lesions can be treated before they
develop into melanoma. Also, if exposures to radiation and chemicals at LLNL have decreased over time
(3), risks associated with those activities would be commensurately reduced. According to
LLNL, melanoma rates in the workforce have fallen to Bay Area averages since 1985.

Although overall cancer rates do not appear to be elevated among the LLNL workforce or community
residents and no elevation of birth defects was noted, there appears to have been an excess of melanoma
in both populations from before 1970 until the mid-1980s. A portion of the excess of melanoma might be
in part due to earlier diagnosis of LLNL employees compared to community members, as publicity about
melanoma possibly prompted heightened awareness in later years. However, as the elevation in
melanoma exceeded the expected numbers among both early stage and invasive tumors, heightened
awareness alone would not be expected to account for the increase.

Within the LLNL workforce, the search for workplace risk factors for the melanoma excess found several
associated factors, including work around sources of ionizing radiation. Although LLNL's study findings
did not include this association, independent researchers confirmed the findings through a re-analysis of
the original data.

In the scientific literature, studies of radiation have had inconsistent results regarding melanoma. This
may be due, in part, to the rare nature of melanoma compared to other skin cancers, or that melanoma
may be less radiosensitive. More recent studies examining various sources of radiation (e.g., x-ray
technicians, pilots and flight attendants [who are exposed to gamma radiation], and those with exposures
from x-rays and radon) now include a number of large and well-conducted studies noting an increased
melanoma risk.

Sources of exposure that would have affected community members are unclear, although it is known that
tritium has been released over time, with most of the large releases from two accidents in the 1965 and
1970. This type of release would affect both LLNL employees and community members. Another
possible exposure pathway to community members is potential contact with plutonium-contaminated
sewage sludge distributed in the community, although the levels have been estimated to be well below a
level required to cause health problems.

Because of the consistent historic elevations of melanoma among the LLNL workforce and the
associations found between exposure to radiation and melanoma in this population, it would be useful for
future epidemiological studies of radiation exposure (not specifically at LLNL) to consider addressing melanoma directly.

RECOMMENDATION

Because the previously elevated rates of melanoma in the community and LLNL have been described as decreasing more recently, data should be periodically reviewed to check the rates of melanoma to see if this trend is continuing.

PUBLIC HEALTH ACTION PLAN

The Public Health Action Plan contains a description of actions taken, to be taken, or under consideration
by ATSDR and CDHS regarding this site. The purpose is to ensure that this health consultation not only
identifies public hazards, but also provides a plan of action designed to mitigate and prevent adverse
human health effects resulting from exposures to hazardous substances in the environment. CDHS and
ATSDR will follow up on this plan to ensure that the actions are carried out.

The California Department of Health Services under a cooperative agreement with the Agency for Toxic
Substances and Disease Registry (ATSDR) prepared the "Review of Health Studies Relevant to Lawrence
Livermore National Laboratory and the Surrounding Community" health consultation. The document is in
accordance with approved methodology and procedures existing at the time the health consultation was prepared.

Tammie McRae, MS
Technical Project Officer, SPS, SSAB, DHAC

The Division of Health Assessment and Consultation, ATSDR, has reviewed this public health consultation and concurs with the findings.

Roberta Erlwein
Chief, State Program Section, DHAC, ATSDR

1 CDHS requested the report this information is based on, but it was not available, per LLNL.2 Using a chi-square test for independence, we found that although a difference between the two time periods (1974-1979 and 1980-1985) might exist, it was not statistically significant. This was true for LLNL as well as in the community. The chi-square test is interpreted using a p-value, which indicates how likely it is that the results occurred by chance. A p-value of less than 0.05 means that the likelihood of a result occurring by chance alone is less than 5%. The chi-square for LLNL resulted in a p-value=0.46, and for the community, p-value=0.32. Both values are well over 0.05, suggesting that the results could have occurred by chance (i.e., there was no difference in lesion thickness between the two time periods, or any difference could have occurred by chance). On the second question regarding lesion thickness at LLNL compared to the community, again, although a difference might exist, statistical testing did not detect a difference in thickness between LLNL lesions and community lesions in either time period (earlier period, p=0.19; later period, p=0.50).3 The author of this report contacted the current
LLNL Medical Director, Dr. James Seward, to obtain information on the original
algorithm and why and how it was changed. The Medical Director reported that he
contacted as many authors of the report as possible, but none could recall the
original algorithm nor why it was changed, but that all persons queried agreed
it was a minor change.